Numerous adamantane-based compounds have been tested for their activity against a number of infectious agents such as bacteria, viruses and as treatments against cancer and parkinson's disease, as well as a means of treating cardiac, circulatory and vascular disease, hypertension, depression and drug-induced extrapyramidal reactions. For a review on this topic, see Chapter 7 in Adamantane, The Chemistry of Diamond Molecules, R. C. Fort, Jr., Marcel Dekker, Inc., 1976.
Adamantane, also known as tricyclo-[3.3.1.1.sup.3,7 ] decane, is a polycyclic alkane with the structure of three fused cyclohexane rings. The ten carbon atoms which define the framework structure are arranged in an essentially strainless manner thereby giving a very stable backbone for the addition of a variety of moieties. Four of these carbon atoms, the bridgehead carbons, are tetrahedrally disposed about the center of the molecule. The other six (methylene carbons) are octahedrally disposed. Because of the particular reactivity of adamantane, functional groups have been readily introduced at the bridgehead 1-, 3-, 5-, 7- positions of adamantane. U.S. Pat. Nos. 5,019,660 to Chapman and Whitehurst and 5,053,434 to Chapman teach diamondoid compounds which bond through the methylene positions of various diamondoid compounds. For a survey of the chemistry of diamondoid molecules, see Adamantane, The Chemistry of Diamond Molecules, Raymond C. Fort, Marcel Dekker, New York, 1976. For synthesis methods for adamantanes, see Paul Schleyer, Cage Hydrocarbons, George A. Olah, ed., Wiley, New York, 1990.
The IUPAC numbering system for adamantane and diadamantane are shown below. ##STR1##
These have been called diamondoid compounds because their structures are part of the diamond lattice.
Certain derivatives of adamantane particularly those with amino substitutions at the (1-) position have been found to demonstrate activity against influenza and herpes, as well as against certain cancers such as angiocarcinoma and pancreatic carcinoma.
U.S. Pat. No. 3,152,180 to Haaf discloses N-tertiary alkyl amines and amides as intermediates for pharmaceutical use. For example, N-(adamantyl-1)-formamide is disclosed.
U.S. Pat. No. 3,342,863 to Hermann discloses certain lower alkyl 1-amino adamantane oxides having the formula ##STR2## where R.sub.1 and R.sub.2 may be C.sub.1-12 alkyl, as useful antiviral agents and antioxidants.
U.S. Pat. No. 3,352,912 to Prichard discloses (1-) substituted adamantane (C.sub.10) derivatives having an aminomethyl or N-substituted aminomethyl group attached to a bridgehead (1-) nuclear carbon atom of adamantane and also (3-) substituted tricyclo [4.3.1.1.sup.3,8 ] undecanes (C.sub.11). The compounds are used as antiviral agents.
British Patent No. 1,063,365 describes adamantane substituted at the (1-) position with a primary or secondary amino group for use against swine influenza.
Chemical Abstracts 104:130230b (1986) lists an Abstract of a Russian article by P. A. Krasutskii et al., "Amino Acids of the Adamantane Series I. Synthesis and Antiviral Activity of Adamantane .alpha. Amino Acids and their Derivatives", Khim.-Farm. Zh 19(7):825-9 (1985) describing adamantane substituted at the (1-), (3-), (5-) and (7-) positions with hydrogen, methyl, or (CH.sub.2).sub.n CH(NH.sub.2)CO.sub.2 H and having the formula ##STR3##
The products were tested using A-- and Sindbis--type viruses. The results are not described in the English Abstract.
More recently, U.S. Pat. No. 5,221,693 to Shetty discloses bis-adamantane based compounds of the formulas ##STR4## in which Z is an adamantane group. All of the compounds require two separate 1-adamantanyl moieties. The compounds are described as having antimicrobial and antiviral uses including against gram-positive and gram-negative bacteria, fungi, yeasts and enveloped viruses such as herpes and retroviruses.
A survey of adamantane compounds which have been tested for pharmacological activity is presented in Adamantane, The Chemistry of Diamond Molecules, Raymond C. Fort, Jr., Marcel Dekker, New York, 1976. Described compounds are adamantanes which are generally amino-substituted at the 1 or 2 position. The 1-aminoadamantanes which include primary and secondary amino functional groups were effective against certain viruses, such as influenza A, B, rous sarcoma, esh sarcoma, sendai, Newcastle, herpes, vaccinia and parainfluenza viruses. The survey discloses that adamantane which was amino-substituted with NHCSNHR at the (2-) position was modestly effective against herpes, vaccinia and Newcastle virus. 3R-Homoadamantane, R=CH.sub.2 NH.sub.2, CH(CH.sub.3)NH.sub.2 or C(CH.sub.3).sub.2 NH.sub.2, had activities similar to 1-aminoadamantane. However, 1-aminoadamantanes which were also substituted at the (3-) position with R=CO.sub.2 H or NH.sub.2 showed no activity; R=OH showed slight activity. 3-CO.sub.2 H-1-AdCH.sub.2 NR.sub.2 also showed no antiviral activity. While 3-R-1-AdNH.sub.2, R=CH.sub.3 or Br showed significant activity.
It is apparent from this survey that antiviral activities of adamantane have derived primarily from certain amino substitutions at the 1 or 2 positions of adamantane or 3-substituted homoadamantanes. It also appears that only analogues with amino substitutions at the (1-) position gave predictable activity.
German Patent DE 3921062 describes using 1-adamantamine hydrochloride in combination with AZT for therapy and prophylaxis of retroviruses such as HIV-1.
In the design of antiviral agents, viruses are targeted at steps in their life cycles. Attempts have been made to interrupt replication of viral nucleic acids in the infected cell or to interrupt the synthesis of viral proteins. However, viral multiplication must be inhibited without the undesirable side effect of damaging the host cells (cytopathic effect). The majority of anti-retrovirals and antivirals have been analogs of deoxyribonucleosides such as AZT, ddI and ddC which are used for HIV infections and which interfere with the synthesis of viral nucleic acids.
Amantadine at higher concentration (&gt;0.5 mM), non-specifically inhibits viral entry into the cell by altering the pH of the endocytic vesicle. At lower concentration (about 5 .mu.M), amantadine exhibits a selective strain-specific inhibition of virus assembly (See, e.g., Hay, A. J. and Zambon, M. C., "Multiple Actions of Amantadine Against Influenza Viruses", in Dev. Mol. Virol. 1984, 4 (Antiviral Drugs and Interferon: The Molecular Basis of Their Activity), Becker, Y., ed., 1984, 301-15. 1-Aminoadamantane hydrochloride (amantadine hydrochloride) is available commercially as an antiviral under the name Symmetrel and is used in the treatment and prevention of influenza A infections. The (1-) position of adamantane has also been substituted with --CH(CH.sub.3)NH.sub.2. The resulting compound is available commercially under the name Rimantadine which is also used in the treatment and prevention of influenza A.
Presently a great deal of research is focused on finding active agents against HIV infection. These agents are also usually targeted at a specific step in the complex life cycle of the virus. By interrupting a specific step in viral replication using therapeutic drugs, it is hoped that symptoms from infection can be at least delayed if not prevented. Most clinical successes to date have focused on the point in the viral life cycle where the genetic material of HIV (RNA) is reverse transcribed into DNA, which then infiltrates the host cell's genes. The drugs AZT, ddI and ddC work in this manner. Other methods for halting the life cycle target the HIV enzyme protease, which is required for assembling newly made HIV particles, or other proteins which govern replication.
Thus far the most effective compounds which have been approved to treat HIV infection act at the reverse transcription step. Presently, there is a need to find therapeutic agents which act at different stages of the viral life cycle. It is hoped that a combination of drugs acting at different steps of the viral life cycle would overcome the development of resistance by the virus. This type of combination drug therapy has been used successfully against intractable bacterial infections such as tuberculosis.
Compounds of the present invention have been found to act at more than one step, that is, either early in the life cycle, or in the later stages of the virus life cycle. These compounds also differ from previously used antiviral amantadine derivatives in that the new compounds have different substituted sites and different substituents at these sites in their structures. Particularly effective compounds in the present invention are diamondoid ketones. Previously, this class of compounds has not been known to have any pharmacological activity whatsoever.
It is an object of the invention to provide a method of inhibiting viruses using new diamondoid compounds.
It is a further object of the invention to provide effective diamondoid antiviral compounds useful in pharmaceutical formulations and in kits.
It is yet another object of the invention to provide diamondoid antiviral compounds effective in treating HIV infections.
It is another object of the invention to provide a method for treating viral infections.
It is still another object to provide an antiviral for use on drinking cups, syringes and specimen containers, birth control devices such as condoms, etc. e.g., as a coating or as an additive, for example, in blood product preparations and similar biologicals.